Disc annulus closure

ABSTRACT

Disclosed herein are methods for treating a defect in a spinal disc nuclear space, comprising: (a) creating an opening by open, percutaneous or laparoscopic techniques to access the defect in the nuclear space; (b) removing a desired amount of tissue from the nuclear space; (c) positioning a delivery catheter through the opening; (d) fluidically isolating the nuclear space by blocking the opening with a blocking component of the catheter; (e) delivering an in-situ curable liquid material through a lumen of the catheter to the nuclear space; and (f) maintaining the isolating until the liquid material has cured. Also disclosed are treatment systems and materials for prostheses.

RELATED APPLICATIONS

This application is a continuation of and claims priority under 35U.S.C. §120 to U.S. Ser. No. 12/152,389, filed May 14, 2008, and claimsthe benefit of priority under 35 U.S.C. §119(e) to U.S. ProvisionalApplication Nos. 60/931,407, filed May 22, 2007, 60/930,064, filed May14, 2007 and 60/930,104, filed May 14, 2007, the disclosures of whichare incorporated herein by reference.

FIELD OF THE INVENTION

This disclosure relates to methods and devices for modifyingintervertebral disc tissue, spaces, and structure. Also disclosed aremethods and devices disclosed relate to the localization of an in situforming nucleus replacement prosthetic, while it is fluid and not fullycured, using open and minimally invasive techniques. The devices forlocalizing the in situ curing implant are catheter-based, and adapttheir cross section to occlude the otomy to the disc nucleus whileproviding for catheter delivery of the fluid implant.

BACKGROUND OF THE INVENTION

Intervertebral disc abnormalities are common in the population and causeconsiderable pain, particularly if they affect adjacent nerves. Discabnormalities result from trauma, wear, metabolic disorders and theaging process and include degenerative discs, localized tears orfissures in the annulus fibrosus, localized disc herniations withcontained or escaped extrusions, and chronic, circumferential bulgingdiscs. Disc fissures occur as a degeneration of fibrous components ofthe annulus fibrosus. Rather minor activities such as sneezing, bendingor simple attrition can tear degenerated annulus fibers and create afissure. The fissures may be further complicated by extrusion of nucleuspulposus material into or beyond the annulus fibrosus. Difficulties canstill present even when there is no visible extrusion, due tobiochemicals within the disc irritating surrounding structures andnerves.

A contained disc herniation is not associated with free nucleusfragments migrating to the spinal canal. However, a contained discherniation can still protrude and irritate surrounding structures, forexample by applying pressure to spinal nerves. Escaped nucleus pulposuscan chemically irritate neural structures. Current treatment methodsinclude reduction of pressure on the annulus by removing some of theinterior nucleus pulposus material by percutaneous nucleotomy. See, forexample, Kambin U.S. Pat. No. 4,573,448. Complications include discspace infection, nerve root injury, hematoma formation, instability ofthe adjacent vertebrae and collapse of the disc from decrease in height.It has been proposed to treat weakening due to nucleus pulposusdeficiency by inserting preformed hydrogel implants. See, Ray U.S. Pat.Nos. 4,772,287; 4,904,260 and, 5,562,736 and Bao U.S. Pat. No.5,192,326.

More recently, delivery of in situ curing liquids to form a solidprosthetic in the nucleus of a disc have been disclosed. The fluid formof these implants enables access to the spine in a minimally invasivemanner, and includes procedures for restoring structural integrity tovertebral bodies. See Scribner U.S. Pat. Nos. 6,241,734 and 6,280,456;Reiley U.S. Pat. Nos. 6,248,110 and 6,235,043; Boucher U.S. Pat. Nos.6,607,554 and Bhatnagar 6,395,007. Methods of repairing the spinal discor portions thereof are disclosed in Cauthern U.S. Pat. No. 6,592,625,Haldimann U.S. Pat. No. 6,428,576, Trieu U.S. Pat. No. 6,620,196 andMilner U.S. Pat. No. 6,187,048.

There are a variety of injectable biomaterials disclosed in issuedpatents including: cross-linkable silk elastin copolymer disclosed inStedronsky U.S. Pat. No. 6,423,333, Capello U.S. Pat. No. 6,380,154,Ferrari U.S. Pat. No. 6,355,776, Stedronsky U.S. Pat. No. 6,258,872,Ferrari U.S. Pat. No. 6,184,348, Ferrari U.S. Pat. No. 6,140,072;Stedronsky U.S. Pat. No. 6,033,654; Ferrari U.S. Pat. No. 6,018,030;Stedronsky U.S. Pat. No. 6,015,474; Ferrari U.S. Pat. No. 5,830,713;Stedronsky U.S. Pat. No. 5,817,303; Donofrio U.S. Pat. No. 5,808,012;Capello U.S. Pat. No. 5,773,577; Capello U.S. Pat. No. 5,773,249;Ferrari U.S. Pat. No. 5,770,697; Stedronsky U.S. Pat. No. 5,760,004;Donofrio U.S. Pat. No. 5,723,588; Ferrari U.S. Pat. No. 5,641,648;Capello U.S. Pat. No. 5,235,041; protein hydrogel described in MorseU.S. Pat. No. 5,318,524; Morse U.S. Pat. No. 5,259,971; Morse U.S. Pat.No. 5,219,328; polyurethane-filled balloons disclosed in Bao U.S. Pat.No. 7,077,865; Bao U.S. Pat. No. 7,001,431; Felt U.S. Pat. No.6,306,177; Felt U.S. Pat. No. 6,248,131; Bao U.S. Pat. No. 6,224,630;collagen-PEG disclosed in Olsen U.S. Pat. No. 6,428,978; Olsen U.S. Pat.No. 6,413,742; Rhee U.S. Pat. No. 6,323,278; Wallace U.S. Pat. No.6,312,725; Sierra U.S. Pat. No. 6,277,394; Rhee U.S. Pat. No. 6,166,130;Berg U.S. Pat. No. 6,165,489; Simonyi U.S. Pat. No. 6,123,687; Berg U.S.Pat. No. 6,111,165; Sierra U.S. Pat. No. 6,110,484; Prior U.S. Pat. No.6,096,309; Rhee U.S. Pat. No. 6,051,648; Esposito U.S. Pat. No.5,997,811; Berg U.S. Pat. No. 5,962,648; Rhee U.S. Pat. No. 5,936,035;Rhee U.S. Pat. No. 5,874,500; chitosan disclosed in Chemte U.S. Pat. No.6,344,488; other polymers discussed in Boyd U.S. Pat. No. 7,004,945;Collins U.S. publication 2006/0004326; Collins U.S. publication2006/0009851; Milner U.S. Pat. No. 6,187,048; Daniell U.S. Pat. No.6,004,782; Urry U.S. Pat. No. 5,064,430; Urry U.S. Pat. No. 4,898,962;Urry U.S. Pat. No. 4,870,055; Urry U.S. Pat. No. 4,783,523; Urry U.S.Pat. No. 4,589,882; Urry U.S. Pat. No. 4,500,700; Urry U.S. Pat. No.4,474,851; Urry U.S. Pat. No. 4,187,852; Urry U.S. Pat. No. 4,132,746.

Delivery of an in situ forming prosthetic to the nuclear space requiresconstructing a passageway into the nucleus and removal of the nucleusfibrosus, in total or in part. The passageway is usually made throughthe annulus, especially when part of the annulus should be removed tocorrect a pathological condition. Whether the passageway is through theannulus or elsewhere, for example, through the vertebral body, there isa risk of the formed nucleus prosthetic extruding through thepassageway. Nucleus prosthetic extrusion can affect the surroundingnerves adversely. Methods of blocking a passageway made through theannulus are disclosed in Lambrecht U.S. Pat. No. 6,425,919, Lambrecht,et al. U.S. Pat. No. 6,482,235, Lambrecht, et al. U.S. Pat. No.6,508,839, Cauthen U.S. Pat. No. 6,592,625, Lambrecht, et al. U.S. Pat.No. 6,821,276 and Lambrecht et al. U.S. Pat. No. 6,883,520. Othermethods of preventing nucleus prosthetic extrusion include enclosing theprosthetic entirely inside of an enveloping sheath and are disclosed inRay, et al. U.S. Pat. No. 4,904,260, Bao, et al. U.S. Pat. No.5,192,326, Kuslich U.S. Pat. No. 5,549,679, Stalcup, et al. U.S. Pat.No. 6,332,894, Wardlaw U.S. Pat. No. 6,402,784, Weber, et al. U.S. Pat.No. 6,533,818, and Reuter, et al. U.S. Pat. No. 6,805,715. Still othermethods of preventing nuclear prosthetic extrusion include delivering apreformed prosthetic in a reduced state, which when introduced into thebody increases in volume. These methods and devices are disclosed inRay, et al. U.S. Pat. No. 6,602,291, Stoy, et al. U.S. Pat. No.6,726,721, and Li, et al. U.S. Pat. No. 6,764,514.

None of the techniques or devices and associated methods of their usedescribed above are entirely satisfactory from either a biocompatibilityor efficacy perspective, for localization of an in situ curing liquidnucleus implant. Accordingly, there remains a need for the developmentof treatment methods and devices for implanting spinal disc prostheses.

SUMMARY OF THE INVENTION

One embodiment provides a method for treating a defect in a spinal discnuclear space, comprising:

(a) creating an opening by open, percutaneous or laparoscopic techniquesto access the defect in the nuclear space;

(b) removing a desired amount of tissue from the nuclear space;

(c) positioning a delivery catheter through the opening;

(d) fluidically isolating the nuclear space by blocking the opening witha blocking component of the catheter;

(e) delivering an in-situ curable liquid material through a lumen of thecatheter to the nuclear space; and

(f) maintaining the isolating until the liquid material has cured.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the invention will be understood from thefollowing description, the appended claims and the accompanyingdrawings, in which:

FIG. 1 is a superior cross sectional anatomical view of a cervical discand vertebra; and

FIG. 2 is a schematic view of an introducer and an embodiment of adelivery catheter having a balloon as a blocking component, in whichsolid lines illustrate the position of the instrument in the absence ofbending forces and dotted lines indicate the position of the distalportion of the instruments under bending forces applied to theintradiscal section of the instrument;

FIG. 3 is a schematic view of another embodiment of a delivery catheterin which the blocking component comprises an elastic collar;

FIG. 4A is a schematic view of a guidewire introduced into the nucleardisc space;

FIG. 4B is a schematic view of a cannula fitted with an obturatorintroduced into the nuclear disc space;

FIG. 4C is a schematic view of a shaver blade introduced into the lumenof the cannula of FIG. 4B;

FIG. 4CD is a schematic view of a delivery catheter introduced into thelumen of the cannula of FIG. 4B; and

FIG. 5 is a schematic view of a cannula moved distally in the annulussuch that the delivery catheter is deployed in contact with the annulustissue.

DETAILED DESCRIPTION

One embodiment provides a device for delivering an in situ curing liquidnucleus implant intended to replace or augment the natural disc nucleusspace. The disc nucleus space includes the nucleus pulposus and theadjacent tissues, including the vertebral endplates and inner layers ofthe disc annulus. Curing with respect to the liquid nucleus implantrefers to a phase change of the implant from liquid to solid. Thetreatment involves delivery of an in situ polymerizing tissue adhesiveinto the treatment area of the nucleus or nuclear space. The treatmentfurther involves a means for preventing migration of the liquid implantafter it has been delivered and before it has fully cured. The deliveryaspects of the device are not intended to remain in the body after theimplant has been delivered and cured.

One embodiment provides a method for treating a defect in a spinal discnuclear space, comprising:

(a) creating an opening by open, percutaneous or laparoscopic techniquesto access the defect in the nuclear space;

(b) removing a desired amount of tissue from the nuclear space;

(c) positioning a delivery catheter through the opening;

(d) fluidically isolating the nuclear space by blocking the opening witha blocking component of the catheter;

(e) delivering an in-situ curable liquid material through a lumen of thecatheter to the nuclear space; and

(f) maintaining the isolating until the liquid material has cured.

In one embodiment, the removing in (b) comprises removing one of (i) aportion of the nucleus pulposus, (ii) all of the nucleus pulposus, or(iii) a portion or all of the nucleus pulposus and a portion or all ofthe inner layers of the annulus fibrosus.

In one embodiment, the device or delivery catheter comprises a lumen,typically of minimal cross section, but sufficiently large to deliverthe liquid nucleus implant by conventional methods. Conventional methodsinclude a syringe or similar liquid dispensing device that is eithermechanically pressurized or manually pressurized sufficiently to deliverthe liquid nucleus implant to the treatment site before the liquidimplant has cured. In one embodiment, the delivery lumen, conventionallya catheter, is fitted with a syringe-type connection, such as a luerconnection.

In one embodiment, the delivery catheter comprises a blocking componentthat sealably interfaces with the access hole made through bone or thedisc annulus. In one embodiment, the blocking component is inflatable,e.g., a balloon surrounding a catheter, where the catheter possesses atleast one lumen for delivery of the liquid nucleus implant and a leastone lumen for controllably inflating the balloon.

In another embodiment, where the blocking aspect is an elastic collarmade to expand by compression along the delivery catheter only one lumenis required.

In one embodiment, the treatment method comprises two or moreapplications of in-situ curable liquid material. The delivery lumen maybe suitably sized to allow a tube to be inserted in the delivery lumento act as a disposable delivery lumen to be removed after a firstdelivery of liquid material has cured and to be subsequently replaced byan additional disposable delivery lumen to enable a second delivery ofliquid implant. This process can be repeated for as many applications ofliquid material desired.

In one embodiment, the proximal and distal ends of the blockingcomponent may be marked with radio-opaque features or other markersuitable for enabling a medical professional to position the blockingaspect relative to a vertebral feature. In another embodiment, a set ofproximal and distal markers suitable for positioning the blockingcomponent in the nucleus annulus provides the proximal end flush withthe inner surface of the annulus or on the margin of a cleared region ofnucleus.

In one embodiment, the treating comprises one or more of:

(i) augmenting or replacing the nucleus pulposus;

(ii) reinforcing a wall of the annulus fibrosus;

(iii) removing and sealing herniated or bulging portions of a disc; and

(iv) closing a defect in the annulus pulposus.

One embodiment provides techniques employing the in situ curing liquidnucleus implant delivery device for modifying the disc annulus,vertebral endplates and/or nucleus to restore nuclear integrity. Openand minimally invasive surgical methods can be used to treat discabnormalities at locations previously not accessible via percutaneousapproaches, and without substantial destruction of the disc and/orsurrounding tissue. The treatment entails delivery of in-situ curableliquid material to select locations within the disc, including deliveryto the location of an annular fissure, the location of a nuclectomy, orthe location of an annulus herniation. In one embodiment, the surgicalmethods disclosed herein involve producing an access to the nucleuspulposus, and delivering an in situ phase-changing liquid to repair theannulus, endplates and/or nucleus.

Establishing the access to the nucleus pulposus may involve apositioning means comprising a needle or guidewire which is directed toa treatment site in the disc, guiding a cutting device to the site wherethe positioning means is located so as to make an access through theannulus or bone, and delivering along the positioning means anoperational port through which the delivery catheter might be deployed.In the case of access through the disc annulus, the operational port mayaccommodate a conically terminated stylet suitable for delivering theoperational port in a minimally disruptive manner to a site within thedisc. Once positioned, the conically terminated stylet is removed and aportion or all of the nucleus pulposus may be removed by conventionalmeans through this port. Once a sufficient quantity of nucleus isremoved the delivery catheter is positioned within the operational portsuch that when the blocking means is deployed, liquid nucleus implantmay be injected into the created nuclear space such that the implantmaterial is prevented from traversing the operational port.

In one embodiment, the delivery catheter does not require a second lumenfor removal of the displaced gas where the implant foams andencapsulates the air at an elevated pressure. Alternatively, an overflowor gas displacement port situated in either the operational port or thedelivery catheter may be employed in the design. Once the liquid implantis cured the catheter and operational port may be removed from the bodyleaving the cut surfaces of the annulus free from implant material andthus disposed to grow together through the natural healing process.

In a further embodiment, it is contemplated that the in-situ curingnucleus implant may be introduced into the nucleus (which may bepreviously evacuated by nucleotomy) to form a reinforced nucleus implantin-situ. Additional nucleus implant may be introduced at the same timeor subsequent to curing of the initial insertion by removing thedelivery catheter only and repositioning a fresh delivery catheter inthe operational port.

In another embodiment, the method further comprises:

(g) removing the blocking component and the delivery catheter; and

(h) closing the opening.

In one embodiment, the proposed methods generally involve one or more ofthe following steps:

-   -   1. Creating an opening by open, percutaneous posterior-lateral,        retroperitoneal, or anterior laparoscopic method. Accessing a        desired portion of spinal disc region through an operational        port can occur in a minimally invasive manner and under the        assistance of a guide wire. The surgical approach selected may        vary depending upon the portion of the spinal disc segment to be        treated.    -   2. Optionally, removing diseased or degenerated tissue while        minimizing removal of healthy tissue while (e.g. removing        bulging portions of the annulus fibrosis, or nucleus pulposis,        removal of osteophytes, etc.)    -   3. Positioning a delivery catheter through the opening. The        positioning can comprise placing the operational port in the        disc annulus by means of insertion of a conical stylet into the        operational port, advancing the operational port into the disc        annulus, removal of the conical stylet, and insertion of a        delivery catheter.    -   4. Fluidically isolating the nuclear space by blocking the        opening with a blocking component of the catheter, (actuation of        the blocking means).    -   5. Delivering an in-situ curable liquid material (e.g., a        polymerizing nucleus implant) through a lumen of the delivery        catheter and into the nuclear space. The delivering can comprise        replacing all or a portion of the disc nucleus (which may have        previously been removed during the same or prior surgery) with        the in-situ curable liquid (polymerizing fluid).    -   6. Maintaining the isolating until the liquid material/implant        has cured. Upon curing, the method can comprise removing the        delivery catheter by deactuation of the blocking means,        retracting the operational port or optionally introducing        another delivery catheter for a second delivery of liquid        polymer and repeating the above steps until suitable replacement        and augmentation of the disc nucleus is achieved.    -   7. Retracting the operational port from the disc annulus,        stopping just outside the disc annulus and optionally providing        a closure means to the otomy (i.e., the surgically created        opening) of the disc annulus and finally removing the        operational port from the body.    -   8. Closing any openings created to gain access to the spine.

In addition to the method, there is provided an in-situ curable liquidmaterial (a liquid nucleus implant) sufficient to provide thetherapeutic effect of strengthening and/or filling the intervertebralspace and preventing extrusion of the polymerized prosthetic. A varietyof in-situ polymerizing liquids may be used, both adhesive andnon-adhesive. In one embodiment, the in-situ polymerizing liquid is asingle-component polyisocyanate based adhesive as described in U.S. Pat.Nos. 6,254,327, 6,296,607, U.S. provisional patent application Ser. No.60/557,314, and U.S. Pub. Nos. 2003/0135238 and 2005/0215748, thedisclosures of which are incorporated herein by reference in itsentirety.

Another embodiment provides a device that has a distal end fitted with adetachable bag that is inserted into the disc and accesses theposterior, posterior lateral and the posterior medial regions of theinner wall of the annulus fibrosus in order to repair an annular fissureat such a location by filling the bag with adhesive.

The present invention generally provides methods and apparatus fortreating intervertebral disc disorders by delivering a liquid nucleusimplant through a delivery catheter to the spinal disc space. The liquidimplant can be delivered within the disc nucleus to repair or replacethe nucleus through a delivery catheter containing a blocking componentto contain or prevent escape of extrusions. The liquid nucleus implantand delivery catheter may also be used to create a disc nucleus implantin-situ. In one embodiment, the methods and devices are used to deliverand reinforce a single-part in-situ polymerizing nucleus implant toaccomplish the desired surgical results.

In one embodiment, a liquid in situ curing agent is delivered via adelivery catheter with a blocking component for fluidically isolating,accessing, and delivering an in-situ curing agent to a location in anintervertebral disc having an annulus fibrosus, the annulus having aninner wall. Additionally, certain embodiments can be used with any of avariety of insertional apparatus to provide proximity to the disc, suchas insertional apparatus known in the art as “introducers”. In oneembodiment, the delivery catheter comprises a lumen that fits snuggly tothe inner surface of the introducer and provides sufficient frictionalretaining and blocking force to remain localized in the introducerduring injection of the liquid nucleus implant. An introducer has aninternal lumen with a distal opening at a terminus of the introducer toallow insertion/manipulation of the operational parts of the deliverycatheter in the interior of a disc.

In one embodiment, the blocking component isolates the tissuessurrounding the opening in the annulus from the liquid implant placed inthe nuclear space to provide for the unobstructed growth of the annulusinto the space created by the opening. In one embodiment, the inner wallof the annulus fibrosus can include the young wall comprised primarilyof fibrous material as well as the transition zone, which includes bothfibrous material and amorphous colloidal gels.

In one embodiment, after the removing in (b), a sheet is interposedbetween the nuclear space and the blocking component to provideincreased strength to the cured liquid implant after it has cured.Exemplary sheets include those described in U.S. Pat. No. 7,044,982 andU.S. Pub. Nos. 2006/0233852, the disclosure of which is incorporatedherein by reference.

The relevant anatomy is illustrated in FIG. 1, which illustrates a crosssectional view of the anatomy of a vertebra and associated disc.Structures of a typical cervical vertebra (superior aspect) are shown inFIG. 1: 104—amina; 106—spinal cord; 108—dorsal root of spinal nerve;114—ventral root of spinal nerve; 118—intervertebral disc; 120—nucleuspulposus; 122—annulus fibrosus; 124—anterior longitudinal ligament;126—vertebral body; 128—pedicle; 130—vertebral artery; 132—vertebralveins; 134—superior articular facet; 136—posterior lateral portion ofthe annulus; 138—posterior medial portion of the annulus; 140—vertebralplate, and 142—spinous process. In FIG. 1, one side of theintervertebral disc 118 is not shown so that the anterior vertebral body126 can be seen.

Liquid Nucleus Implants

One embodiment provides methods for use of a liquid nucleus implant torepair defects in a disc, including repair of the annulus and/or fillingof a nuclear space. Regarding the nucleus implant, a liquid material isintroduced into the intervertebral space to improve the function of thedisc tissues and fluids contained therein. In one embodiment, the liquidnucleus implant has a low viscosity and is capable of delivery through asmall diameter needle, cannula or catheter, for example through atypical catheter having an inner diameter ranging from 3.5 to 5 mm (butsmaller diameter devices can be used if viscosity is sufficiently low.)Low viscosity can be useful in one or more of the following: 1) ease ofdelivery, 2) timely delivery, 3) prevention of delayed pressuretransference from source to the target tissue site, and 4) permitssensing of resistance feedback by the operator to determine appropriatedelivery volumes.

In one embodiment, the viscosity of the curable liquid material is lessthan 1000 cp, such as an implant viscosity of less than 200 cp. Inanother embodiment, the viscosity ranges from 100 cp to 1000 cp. In oneembodiment, the viscosity limit of 1000 cp is satisfied when prepolymeris mixed with water in the ratio of 70:30 or less, and 60:40 or less forthe 200 cp limit.

In one embodiment, the liquid nucleus implant is a single-component,self-curing adhesive that polymerizes in-situ forming internal crosslinks as well as bonds to surrounding tissue and bone. Asingle-component implant is one in which the composition of the implantis substantially the same during all phases of delivery; and,specifically is not an implant that has more than one tissue reactivecomponent. A single-component implant may be mixed with one or moredilutive agents to aid in implant delivery provided the ratio of diluentto active component is not critical to the curing of the implant. Animplant component is any combination of chemical species that can bestored at room temperature without substantial chemical change andremain homogenous in combination. For example, sodium chloride and waterwhen mixed form an implant component commonly known as saline.Specifically, a single-component implant may be a mixture of any numberof implant components provided only one is tissue reactive. A tissuereactive implant component is any implant component with a tissuebiocompatibility as assessed by ISO 10993 different from that ofphysiologic saline.

In one embodiment, the single-component in-situ curable liquid materialcomprises a prepolymer An example of a single-component in situpolymerizing implant is one in which polymerization of the prepolymer,which can be a tissue reactive component, is initiated either by aqueousfluids present in the tissue or by addition of physiological saline orother inert medicinal solution before delivery to the target site. Inone embodiment, the polymerization of a single-component implant doesnot require the addition of cross linkers, catalysts, chain extenders,or complementary components of an adhesive composition. In oneembodiment, cross linking and tissue bonding is mediated either byaqueous fluids present in the tissue, or by premixing of the adhesivewith physiological saline or other medicinal saline solution at the timeof administration. The polymerization time of adhesives is variable, andcan be in the range of about 30 seconds to 30 minutes or more, dependingon the application. Exemplary prepolymers are described in U.S. Pat. No.6,254,327, and U.S. Pub. Nos. 2003-0135238 and US 2004-0068078, thedisclosures of which are incorporated herein by reference.

Polymerization time can be adjusted by selection of properties andcomponents of the liquid nucleus implant. In one embodiment, the tissuereactive single component is a liquid comprising a polyisocyanate-cappedpolyol, typically macromolecular in size, having a mean molecular weightof about 1000 Daltons or more, more typically at least about 4000Daltons, and yet more typically in a range of about 4500 D to about10,000 D, depending on application. Higher molecular weight macromersmay be of use in adhesives having great pliability (and lower tensilestrength). In another embodiment, the liquid nucleus implant furthercomprises a low-molecular weight polyisocyanate, for example with amolecular weight less than about 1000 D. This may comprise thepolyisocyanate used to cap the polyols. This low molecular weightpolyisocyanate may be present in an amount ranging from 1% to 5% of thecomposition. The capped polyol can be multifunctional, and typically atleast partially trifunctional or higher. The polyol may be any ofvarious biocompatible substances such as polyethylene oxide,polypropylene oxide, polyethylene glycol, and copolymers of these. Inone embodiment, the polyol has about 10% to about 30% by weightpropylene oxide subunits, and the rest ethylene oxide.

In one embodiment, the polyisocyanate is typically difunctional. In oneembodiment, the composition is a fast reacting formulation comprising anaromatic diisocyanate such as toluene diisocyanate. In anotherembodiment, the low reacting formulations comprise an aliphaticdiisocyanate such as isophorone diisocyanate. The polymerization timecan be adjusted by selection of appropriate molecular weight polyols.The higher molecular weight polyols produce lower viscosity cappedreaction products and faster reacting solutions. Combinations of theabove species are considered to comprise a single component when theyare stable and remain homogenous while stored at room temperature.

The tissue reactive component of a single-component in situ curingimplant is typically called a prepolymer. The cure times of a prepolymerachieved using the approaches described above depend, in part, oncontrolling one or more of the rate of water diffusion into theprepolymer, the rate of isocyanate to amine conversion, and the activityof the isocyanate-functionalized ends. There are variousnon-tissue-reactive additions to the prepolymer that can be made at thetime of application to speed prepolymer curing. For example, when wateris added to the prepolymer just before application, the cure timedependence on water diffusion is reduced. Generally, addition of waterin volumetric ratios of approximately 1:1 volumetric ratio with theprepolymer maximally reduces cure time. When additional water is added,such as 4:1 volumetric ratio of water to prepolymer, the cure timeincreases from its fastest mixed cure time because the polymer densitydecreases. Similarly, when using higher concentrations of prepolymer,such at 80% or more by volume, the cure time increases from its fastestcure time because the water availability decreases. However, allmixtures with water, from 1% up to about 95% by volume, cure faster thanapplication of prepolymer placed directly on tissue.

In one embodiment, cure times can span as long as 1 hour and as short as30 seconds, although longer cure times are possible. In general, accesswill have been made to the implantation site, and preparation of theimplantation site completed before the liquid implant is prepared. Inone embodiment, the liquid implant is prepared by mixing between twosyringes bridged by a female-to-female luer lok connection prepolymer inone syringe and saline or other suitable aqueous solution in the othersyringe. In one embodiment, the hydrophilic nature of the prepolymerachieves homogenous mixing in approximately 10 mix cycles for mix ratiosof 10-90% prepolymer. In one embodiment, all implant ratios arehomogenous after 20 mix cycles. In one embodiment, the fastest cure timeare achieved where the mix ratio is approximately 1:1. However, the curetime does not differ by more than 100% for all mix ratios.

The surgeon typically requires a cure time long enough to mix and injectthe liquid implant and short enough to provide for in situ curing withina few minutes after implantation. In one embodiment, the cure timeranges from 1 to 10 minutes, such as from 3 to 5 minutes. In oneembodiment, the cure time halves for every 10 degree centigrade increasein mixture temperature. The typical difference between body temperatureand room temperature is about 10° C. Often, there is a decrease in curetime once the liquid implant is injected in the body.

The first action of water with an isocyanate capped prepolymer is toconvert some of the active isocyanate ends on the isocyanate cappedpolyol and some of the active isocyanate ends on the free isocyanate toamine groups. Amine groups react with other isocyanate groups to causerapid chain extension and eventual crosslinking. Therefore, reduced curetimes can also be achieved by substituting some or all of the wateradmixture with aqueous amines. However, in the case of the admixture oftissue reactive amines such a mixture is no longer considered asingle-component implant.

In one embodiment, the prepolymer is an aromatic isocyanate made by endcapping a deionized, dried polyalkylene diol with toluene diisocyanate(TDI), and then reacting the end-capped diol with a deionized driedtriol. In one embodiment, the diol is a polyethyleneglycol/polypropylene glycol co-polymer (random, block or graft), with EO(ethylene oxide) and PO (propylene oxide) in weight ratios ranging fromabout 95:5 to about 25:75, e.g., about 75% EO and 25% PO. An exemplarytriol is trimethylol propane (TMP). An exemplary composition is thereaction product of from about 25% to 35% TDI, from about 65% to 75%diol (75% EO: 25% PO) and from about 1% to about 8% TMP. In oneembodiment, the composition is the reaction product of about 30% TDI,about 70% of the 75:25 diol, and about 1% to about 2% TMP. Theprepolymer can have a mean molecular weight of 4500 to 5500 Dalton.

These prepolymers can have the added advantage of being water-soluble.Their water solubility enables them to be injected into tissue topolymerize the tissue; or, alternatively or additionally to solidify asgels to stabilize tissue or structures. The prepolymer acts as aself-sealing fluid when injected into body cavities.

Isocyanate-capped polyols, while suitable, are not the sole adhesives orin situ curing non-adhesive compositions that can be used. In oneembodiment, the adhesive is hydrophilic and water-soluble before beingcrosslinked. This hydrophilicity can enable the adhesive to be injectedinto tissue to polymerize in contact with, and bond to, the tissue, asadhesive and/or as local bulking agent to fill gaps or fissures, or tostabilize implants. The adhesive can act as a self-sealing fluid wheninjected into cavities or gaps. Once cured in situ, the hydrophilicadhesive can absorb fluid from the tissue, forming a structure that willbe at least somewhat gel-like in character. The cured adhesive can swellto a controlled extent, exerting a controlled amount of local pressure.The tensile properties of the cured adhesive can be adjusted so that theadhesive, like the native tissues of the annulus or of the nucleus,deforms under pressure while exerting a restorative force on thesurrounding structures. Hence, the adhesive-tissue composite tends toreturn to its original shape and location after movement of the spineand is characteristically elastic. These properties can be controlled bythe composition of the adhesive, or by providing a controlled degree ofdilution with saline at the time of administration. This is in contrastwith rigid materials, which tend to fracture rather than yield, and toflowable media, which have no tendency to return to their original shapeafter relaxation of stress. In particular, hydrophobic adhesives tend tobecome rigid, favoring fracture of the cured adhesive at the surface ofthe tissue or implant. They also tend not to bond to tissue, which ishighly hydrophilic.

In situ polymerization of a liquid nucleus implant can comprise twophase changes. The first phase change is the conversion of the liquidimplant into an elastic solid, e.g., a relatively low modulus gel. Inone embodiment, the gel modulus ranges from 0.5 to 20 MPa, from 0.5 to10 MPa, from 0.5 to 5 MPa, from 1 to 5 MPa, from 1 to 3 MPa, or from 1.5and 3 MPa. The suitability of the implant modulus is somewhat dependentupon the size of the otomy (surgically created opening) made in theannulus or vertebral body in order to deliver the liquid implant. Thelarger the otomy, the higher is the minimum acceptable modulus. Theminimum acceptable modulus is also determined by the extent of tissuebonding achieved by the implant curing, the higher the bond strength thelower the minimum acceptable modulus.

The second phase change is the conversion of part of the liquid implantinto a gas phase, which when released and entrapped during curingresults in an elastic gel foam. In one embodiment, the ratio of gasphase to gel phase volume is 10 to 0.1, e.g., 5 to 0.5, or 3 to 1. Thegas phase component of the curing implant can ensure intimate contactbetween implant and surrounding tissue, and specifically the reductionor elimination of air pockets or the need for elaborate venting aspectsof the delivery means to accomplish the same.

The uncured liquid implant can be polymeric in nature, as opposed tobeing a low molecular weight monomer before curing, such as acyanoacrylate. A number of known polymers are potentially useful in thesynthesis of suitable adhesive prepolymers. The polymers can behydrophilic, for example, sufficiently hydrophilic to swell in water. Asuitable range of swelling can be, at atmospheric pressure, between from5% to about 100%, and more typically is from about 5% to about 30%. Inone embodiment, the prepolymers are sufficiently hydrophilic to havesubstantial solubility in water, such as, for instance, 1 g/l or more,e.g., 10 g/l or more, or 100 g/l or more.

The cured implant may be stable in the body, or may degrade in the bodyto smaller, excretable molecules (“degradable”). A wide variety oflinkages are known to be unstable in the body. These include, withoutlimitation, esters of hydroxy acids, particularly alpha and beta hydroxycarboxylic acids; esters of alpha and beta amino acids; carboxylic acidanhydrides; phosphorous esters; and certain types of urethane linkages.In one embodiment, the cured implant is stable in the body for prolongedperiods, as the fibrous materials of the annulus have very limitedself-repair capabilities, and the nucleus has virtually none. However,if methods are found to enhance natural biological repair of the nucleusor annulus, then degradable adhesives or fillers could be used.

The prepolymers can also have reactive groups covalently attached tothem, or part of the backbone. The reactive groups are suitable forreaction with tissue, and for crosslinking in the presence of water orcomponents of bodily fluids, for example water and protein. Suitablegroups include isocyanate, isothiocyanate, anhydrides and cyclic imines(e.g., N-hydroxy succinimide, maleimide, maleic anhydride), sulfhydryl,phenolic, polyphenolic, and polyhydroxyl aromatic, and acrylic or loweralkyl acrylic acids or esters. Such reactive groups are most commonlybonded to a preformed polymer through suitable linking_groups in thepolymer. Commonly found linking_groups include, without limitation,amines, hydroxyls, sulfhydryls, double bonds, carboxyls, aldehydes, andketone groups. Of these groups, aliphatic hydroxyls are among the mostwidely used.

Thus, suitable base polymers include poly(alkyl)acrylic acids andpolyhydroxyalkyl acrylates, polysaccharides, proteins, polyols,including polyetherpolyols, polyvinyl alcohol, and polyvinylpyrrolidone,and these same structures with amine or sulfur equivalents, such aspolyethyleneimine, aminosugar polymers, polyalkylamine substitutedpolyethers, and others. Any of these polymers can be substituted withtwo or three reactive groups, as is required to form a crosslinkablepolymer. When there are many substitutable linking groups, as withpolysaccharides, only a few of the substitutable groups (here, mostlyhydroxyls) should be substituted, and the derivatized polymer will havea somewhat random substitution. In one embodiment, the hydrophilicpolymer will have only a few substitutable linking groups. Polyetherpolyols grown on glycol or amine starters will typically have reactivegroups only at the end of the polyether chains, allowing for detailedcontrol of stoichiometry. Such polymers can be used. In one embodiment,the base polymer is a polymer of ethylene glycol, or a copolymer ofethylene glycol with one or more of propylene glycol, butylene glycol,trimethylene glycol, tetramethylene glycol, and isomers thereof, whereinthe ratio of ethylene glycol to the higher alkanediol in the polymer issufficient to provide substantial water solubility at room or bodytemperature. Such polymer substrates can be synthesized by knownmethods. More typically, preformed polyetherpolyols are purchased,optionally in a prequalified medical grade, from any of numerouscatalogs or manufacturers.

In one embodiment, the prepolymer comprises a polyisocyanate-cappedpolymeric polyol and a small amount of free poly isocyanate. Suchmaterials and their synthesis are described in detail in U.S. Pat. No.6,524,327, the disclosure of which is incorporated herein by reference.The small amount of excess polyisocyanate, typically of molecular weightless than about 1000 Daltons, maximizes the reactivity of the polyols,and by directly and rapidly reacting with tissue, promotes bonding ofthe adhesive to tissue. Typically the small isocyanate contains up toabout 3% of the number of active isocyanate groups on the polymer. Thesmall isocyanate may be all or part low molecular weight capped diol.The capped polyol is multifunctional, and typically is trifunctional ortetrafunctional, or a mixture of trifunctional and/or tetrafunctionalwith difunctional. The polyol can be at least in part a polyether polyolas described above.

The polyisocyanate is typically difunctional, but tri- ortetrafunctional, or star, forms of isocyanate are known and can beuseful. Branching (tri- or tetra-functionality) may be provided by atrifunctional polymer, or by providing a tri- or tetrafunctional lowmolecular weight polyol, such as glycerol, erthyritol or isomer, ortrimethylolpropane (TMP). Fast reacting formulations use an aromaticdiisocyanate such as toluene diisocyanate. Slow reacting formulationsuse an aliphatic diisocyanate such as isophorone diisocyanate. Manyadditional diisocyanates are potentially useful. Some are listed in U.S.Pat. No. 6,524,327, and these and others are found in chemical catalogs,for example from Aldrich Chemical. Alternatively, the polymerizationtime can be adjusted by selecting appropriate molecular weight polyols.The higher molecular weight polyols produce lower viscosity cappedreaction products and slower reacting solutions. However, at anymolecular weight of the polyol(s), the reaction rate is mostsignificantly determined by the reactivity of the functional end groupattached to the polyol.

In one embodiment, the prepolymer is liquid at room temperature (ca. 20°C.) and body temperature (ca. 37° C.), for ease of administration and ofmixture with additives, etc. The prepolymer is stable in storage at roomtemperature, when protected from moisture and light.

The prepolymer may be supplemented by the addition, during manufactureor at the time of administration, of ancillary materials. These mayinclude reinforcing materials, drugs, volume or osmotic pressurecontrolling materials, and visggggggualization aids for optical,fluoroscopic ultrasound or other visualization of fill locations.Reinforcing materials may include particulate materials, fibers, flocks,meshes, and other conventionally used reinforcers. These can becommercial materials approved for in vivo medical use. Visualizationmaterials include a wide variety of materials known in the art, such as,among others, small particles of metals or their oxides, salts orcompounds for fluoroscopy, gas-filled particles for ultrasound, and dyesor reflecting particles for optical techniques.

Osmotic properties can be adjusted for immediate or long-term effects.In one embodiment, the polyether polyol isocyanates have little ioniccharge either before or after polymerization. However, in somesituations, as described below, it is desirable to have a controlleddegree of swelling in water after curing. This can be controlled in partby the ratio of ethylene glycol to other polyols in the formulation. Itcan also be adjusted by adding charged groups to the formulation. Asimple method is to add charged polymers or charged small molecules tothe adhesive at the time of application, for example dissolved in anaqueous solution. Charged polymers, such as polyacrylic acids, willreact poorly with the isocyanates, but will tend to be trapped in thepolymerized matrix. They will tend to increase the swelling of the curedmaterial. In turn, this would allow the use of higher proportions ofnon-ethylene glycol monomers in the polyols. Alternatively, charge couldbe introduced by addition of hydroxy carboxylic acids, such as lacticacid, or tartaric acid, during synthesis or during administration. Addedpolymers could instead be polyamines, but, to avoid rapidpolymerization, should be tertiary or quaternary amines or other aminetypes that will not react with isocyanate. A method of increasingswelling is to incorporate higher concentration of diffusible ions, suchas soluble salts—e.g., sodium chloride—into the adhesive at the time ofapplication. The salt will attract water into the adhesive polymers;after polymerization, the salt will diffuse away and the gel will remainexpanded.

The prepolymer can be adjusted in several ways to optimize its post-cureproperties for the particular situation. In one embodiment, a method ofadjustment of properties is dilution of the polymer with water, saline,or other aqueous solution. A typical dilution would be in the range of5% or less (volume of saline in liquid polymer), for formation of dense,high-tensile, low-swelling deposits, up to about 95% (19 vol.saline/vol. polymer) for readily swelling, highly compliant deposits orbonds. In formulation, allowance should be made for the amount of waterthat will flow into the adhesive from the tissue during reaction. Thiswill usually be relatively small for bulk deposits, but is of moreconcern for thin adhesive layers. In thin layers, fast-curingcompositions can be used, such as compositions with a higher proportionof aromatic diisocyanates. In general, dilution will reduce the tensilestrength and the modulus. The amount of dilution will tend to bedifferent depending on whether the modulus or tensile strength is tomatch that of the annulus (higher) or the nucleus (lower).

Various non-reactive ingredients can be added to the polymer solutioneither in the prepolymer or in the aqueous solution to alter thehydrogel mechanical properties, e.g., tensile strength, elasticity andbubble size. Inert particulate such as tantalum powder will result inbubble nucleation and a finer bubble size, increase the modulus of thehydrogel, and make the hydrogel radio opaque. Emulsifiers can be addedto increase mix homogeneity, reduce bubble size, and provide a higherelongation at break. It is possible to use the same diol used toconstruct the prepolymer as an emulsifier. Alternatively, a higher orlower molecular weight diol may be used. The ratio of EO/PO can bealtered to increased mixability, or pure forms of EO or PO can be used.

Other adjustable factors include the molecular weight of the polymer,and its degree of branching; and its hydrophilicity, which is a functionof the particular polyol or polyols used in the formulation. Inaddition, additives, as described above, can also influence theseproperties.

Compositions

One embodiment provides a liquid preparation for use in medicine, andits uses therein. The liquid preparation contains a reactive polymer,which comprises a “base polymer” or “backbone polymer”, reactive groupson the backbone polymer, and a slight excess of “free” (low molecularweight) polyreactive molecules. The liquid composition is prepared by amethod requiring no catalysts and essentially no solvent. The reactiveliquid polymer is self-curing when applied to tissue, by absorption ofwater and other reactive molecules from the tissue. The cured polymer isused to seal tissue to tissue, or to devices; to apply a protectivecoating to tissue; to form an implant within or upon tissue; to deliverdrugs. The cured polymer is optionally provided with biodegradablegroups, and has a controllable degree of swelling in bodily fluids.

Backbone Polymers

The backbone polymer will comprise a polymeric segment, of molecularweight about 500 D or more, e.g., about 1000 to about 10,000 D, or up toabout 15 kD or 20 kD. The backbone polymer will contain groups that canbe easily derivatized (“capped”) to form the final reactive group. Suchgroups can be alcohols or amines, or optionally sulfhydryls or phenolicgroups. Examples include polymers such as a polymeric polyol, oroptionally a polymeric polyamine or polyamine/polyol. In one embodiment,the polyols are polyether polyols, such as polyalkylene oxides (PAOs),which may be formed of one or more species of alkylene oxide. The PAO,when comprising more than one species of alkylene oxide, may be arandom, block or graft polymer, or a polymer combining these modes, or amixture of PAO polymers with different properties. Exemplary alkyleneoxides are ethylene oxide and propylene oxide. Other oxiranes may alsobe used, including butylene oxide. PAOs are typically made bypolymerization onto a starter molecule, such as a low molecular weightalcohol or amine, e.g., a polyol. Starting molecules with two, three,four or more derivatizable alcohols or other derivatizable groups can beused. The multi-armed PAOs obtained from such starters will typicallyhave one arm for each group on the starter. PAOs with two, three or fourterminal groups can be used. Mixtures of PAOs or other backbonepolymers, having variable numbers of arms and/or variation in otherproperties, are contemplated.

Common polyols useful as starters are aliphatic or substituted aliphaticmolecules containing a minimum of 2 hydroxyl or other groups permolecule. Since a liquid end product is desired, the starters can be oflow molecular weight containing less than 8 hydroxyl or other groups.Suitable alcohols include, for illustration and without limitation,adonitol, arabitol, butanediol, 1,2,3-butanetriol, dipentaerythritol,dulcitol, erythritol, ethylene glycol, propylene glycol, diethyleneglycol, glycerol, hexanediol, iditol, mannitol, pentaerythritol,sorbitol, sucrose, triethanolamine, trimethylolethane,trimethylolpropane. Small molecules of similar structures containingamines, sulfhydryls and phenols, or other groups readily reactive withisocyanates, are also useable.

The PAO, or other backbone polymer, may optionally incorporate non-PAOgroups in a random, block or graft manner. In particular, non-PAO groupsare optionally used to provide biodegradability and/or absorbability tothe final polymer. Groups providing biodegradability are well known.They include hydroxy carboxylic acids, aliphatic carbonates,1,4-dioxane-2-one (p-dioxanone), and anhydrides. The hydroxy carboxylicacids may be present as the acid or as a lactone or cyclic dimmer, andinclude, among others, lactide and lactic acid, glycolide and glycolicacid, epsilon-caprolactone, gamma-butyrolactone, anddelta-valerolactone. Amino acids, nucleic acids, carbohydrates andoligomers thereof can be used to provide biodegradability. Methods formaking polymers containing these groups are well known, and include,among others reaction of lactone forms directly with hydroxyl groups (oramine groups), condensation reactions such as esterification driven bywater removal, and reaction of activated forms, such as acyl halides.The esterification process involves heating the acid under reflux withthe polyol until the acid and hydroxyl groups form the desired esterlinks. The higher molecular weight acids are lower in reactivity and mayrequire a catalyst making them less desirable.

The backbone polymers may also or in addition carry amino groups, whichcan likewise be functionalized by polyisocyanates. Thus, the diaminederivative of a polyethylene glycol could be used. Low molecular weightsegments of amine containing monomers could be used, such asoligolysine, oligoethylene amine, or oligochitosan. Low molecular weightlinking agents, as described below, could have hydroxyl functionality,amine functionality, or both. Use of amines will impart charge to thepolymerized matrix, because the reaction product of an amine with anisocyanate is generally a secondary or tertiary amine, which may bepositively charged in physiological solutions. Likewise, carboxyl,sulfate, and phosphate groups, which are generally not reactive withisocyanates, could introduce negative charge if desired. A considerationin selecting base polymers, particularly other than PAOs or others thatreact only at the ends, is that the process of adding the reactivegroups necessarily requires adding reactive groups to every alcohol,amine, sulfhydryl, phenol, etc. found on the base polymer. This cansubstantially change the properties, particulaly the solubilityproperties, of the polymer after activation.

Reactive Groups

The base or backbone polymer is then activated by capping with lowmolecular weight (LMW) reactive groups. In one embodiment, the polymeris capped with one or more LMW polyisocyanates (LMW-PIC), which aresmall molecules, typically with molecular weight below about 1000 D,more typically below about 500 D, containing two or more reactiveisocyanate groups attached to each hydroxyl, amine, etc of the basemolecule. After reaction of the LMW-PIC with the backbone, each capablegroup of the backbone polymer has been reacted with one of theisocyanate groups of the LMW-PIC, leaving one or more reactiveisocyanates bonded to the backbone polymer via the PIC. The LMW-PIC arethemselves formed by conjugation of their alcohols, amines, etc. withsuitable precursors to form the isocyanate groups. Starting moleculesmay include any of those mentioned above as starting molecules forforming PAOs, and may also include derivatives of aromatic groups, suchas toluene, benzene, naphthalene, etc. Exemplary LMW-PIC for activatingthe polymer are di-isocyanates, e.g., particular toluene diisocyanate(TDI) and isophorone diisocyanate, both commercially available. When adiisocyanate is reacted with a capable group on the base polymer, one ofthe added isocyanates is used to bind the diisocyanate molecule to thepolymer, leaving the other isocyanate group bound to the polymer andready to react. As long as the backbone polymers have on average morethan two capable groups (hydroxyl, amine, etc.), the resultingcomposition will be crosslinkable.

A wide variety of isocyanates are potentially usable as LMW-PICS.Suitable isocyanates include 9,10-anthracene diisocyanate,1,4-anthracenediisocyanate, benzidine diisocyanate, 4,4′-biphenylenediisocyanate, 4-bromo-1,3-phenylene diisocyanate, 4-chloro-1,3-phenylenediisocyanate, cumene-2,4-diisocyanate, cyclohexylene-1,2-diisocyanate,cyclohexylene-1,4-diisocyanate, 1,4-cyclohexylene diisocyanate,1,10-decamethylene diisocyanate, 3,3′ dichloro-4,4′biphenylenediisocyanate, 4,4′diisocyanatodibenzyl, 2,4-diisocyanatostilbene,2,6-diisocyanatobenzfuran, 2,4-dimethyl-1,3-phenylene diisocyanate,5,6-dimethyl-1,3-phenylene diisocyanate, 4,6-dimethyl-1,3-phenylenediisocyanate, 3,3′-dimethyl-4,4′diisocyanatodiphenylmethane,2,6-dimethyl-4,4′-diisocyanatodiphenyl,3,3′-dimethoxy-4,4′-diisocyanatodiphenyl, 2,4-diisocyantodiphenylether,4,4′-diisocyantodiphenylether, 3,3′-diphenyl-4,4′-biphenylenediisocyanate, 4,4′-diphenylmethane diisocyanate, 4-ethoxy-1,3-phenylenediisocyanate, ethylene diisocyanate, ethylidene diisocyanate,2,5-fluorenediisocyanate, 1,6-hexamethylene diisocyanate, isophoronediisocyanate, lysine diisocyanate, 4-methoxy-1,3-phenylene diisocyanate,methylene dicyclohexyl diisocyanate, m-phenylene diisocyanate,1,5-naphthalene diisocyanate, 1,8-naphthalene diisocyanate, polymeric4,4′-diphenylmethane diisocyanate, p-phenylene diisocyanate,4,4′,4″-triphenylmethane triisocyanate, propylene-1,2-diisocyanate;p-tetramethyl xylene diisocyanate, 1,4-tetramethylene diisocyanate,toluene diisocyanate, 2,4,6-toluene triisocyanate, trifunctional trimer(isocyanurate) of isophorone diisocyanate, trifunctional biuret ofhexamethylene diisocyanate, and trifunctional trimer (isocyanurate) ofhexamethylene diisocyanate.

In general, aliphatic isocyanates will have longer cure times thanaromatic isocyanates, and selection among the various availablematerials will be guided in part by the desired curing time in vivo. Inaddition, commercial availability in grades suitable for medical usewill also be considered, as will cost. Toluene diisocyanate (TDI) andisophorone diisocyanate (IPDI) can be used. The reactive chemicalfunctionality of the liquid implants can be isocyanate, but mayalternatively or in addition be isothiocyanate, to which all of theabove considerations will apply.

Physical Properties

The polymerizable materials are typically liquids at or near bodytemperature (i.e., below about 45 deg. C.), and can be liquid at roomtemperature, ca. 20-25 deg. C., or below. The liquids are optionallycarriers of solids. The solids may be biodegradable or absorbable. Theliquid polymerizable materials are characterized by polymerizing uponcontact with tissue, without requiring addition of other materials, andwithout requiring pretreatment of the tissue, other than removing anyliquid present on the surface(s) to be treated. A related property ofthe polymerizable materials is that they are stable for at least 1 yearwhen stored at room temperature (ca. 20-25 degrees C.) in the absence ofwater vapor. This is because the material has been designed so that boththe reaction that polymerizes the polymers, and the reactions thatoptionally allow the polymer to degrade, both require water to proceed.

In contrast to previous formulations, the polymeric polyisocyanatescontain a low residual level of low molecular weight (LMW)polyisocyanates (PIC). For example, the final concentration of LMW-PICisocyanate groups in the formulation, expressed as the equivalentmolarity of isocyanate groups attached to LMW compounds, is normallyless than about 1 mM (i.e., 1 mEq), e.g., less than about 0.5 mEq and orless than about 0.4 mEq. In one embodiment, the level of LMW isocyanategroups is finite and detectable, for example greater than about 0.05mEq, or greater than about 0.1 mEq. In one embodiment, a low but finitelevel of LMW-PIC molecules tends to promote adherence between theapplied polymer formulation and the tissue being treated. However,decreased levels of LMW-PIC may tend to decrease tissue irritationduring application and cure of the liquid polymer preparation. In oneembodiment, the range of about 1 mEq to about 0.05 mEq is approximatelyoptimal. In situations requiring tissue adherence in the presence ofbiological fluid, or in adherence to difficult tissues, greater levelsof LMW-PIC isocyanate groups may be used.

Swellability

The active prepolymers may form intertwined polymer chains afterreaction that may change their intertwined geometry under action byfluids within the body. In particular, one or more components may causethe formed polymeric material, whether as coating, adhesive, or solid,to swell. Swelling may have several consequences, and can be controlled.In one mode, swelling can lead to subsequent break-up (physicaldisintegration) of an implant or other final form, rendering the entireimplant absorbable. Or, one or more of the components may dissolve inthe body rendering the remaining components absorbable. (Dissolvablematerials could be added as solids, or as nonreactive polymers dilutingthe reactive components.) Or, one or more components may bebiodegradable rendering the remaining components absorbable. Forexample, liquids containing a polyethylene/polypropylene random coblockpolyol capped with polyisocyanate are capable of forming elastic gelswith water content as high as 90%. When these polyethylene/polypropylenepolyols are esterified with a carboxylic acid and reacted with atrifunctional molecule such as trimethylolpropane, or alternatively whenthe trifunctional molecule is esterified and reacted with diols ofpolyethylene/polypropylene, useful activated polyols are formed. Thesepolyols, when end capped with a polyisocyanate are capable of forminggels or solids in a living organism that decrease in volume and strengthover time.

However, the ratio of propylene oxide to ethylene oxide can be varied,and the two monomers can be polymerized into block copolymers, randomcopolymers, or graft copolymers. These types are commercially available.While the ethylene oxide groups tend to absorb water, and so to swellthe crosslinked material formed in the body, the propylene oxide groupsare less hydrophilic, and tend to prevent swelling in aqueous fluids.Thus, the degree of swelling of the polymerized material in water can becontrolled by the design of the reactive polymers. Another route ofswelling control is by incorporation of non-PAO groups, such asaliphatic or aromatic esters, into the polymer (as, or in addition to,esters used to confer degradability.)

The prepolymer can be formed by capping the polyols (as backbonepolymer) with polyisocyanate, preferably a diisocyanate. However,suitable isocyanates have the form R(NCO)_(x), where x is 2 to 4 and Ris an organic group. Another approach to creating an in situpolymerizing liquid that biodegrades in the body is to graft the polyolonto a biodegradable center. Suitable polymers for inclusion as centermolecules are described in U.S. Pat. No. 4,838,267. They includealkylene oxalates, dioxepanone, epsilon-caprolactone, glycolide,glycolic acid, lactide, lactic acid, p-dioxanone, trimethylenecarbonate, trimethylene dimethylene carbonate and combinations of these.

The center molecule may be a chain, a branched structure, or a starstructure. Suitable star structures are described in U.S. Pat. No.5,578,662. Isocyanate capped alkylene oxide can be reacted with thesemolecules to form one or more extended chains. The ends of these chainscan therefore participate in crosslinking with other centers or bond totissue.

Center molecules such as those listed above will form rigid solids uponpolymerization. Therefore, it is generally more useful to ensure atleast 80% alkylene oxide is in the final polymerized structure.Furthermore, the alkylene oxide should be comprised of at least 70%ethylene oxide.

These criteria ensure that the polymerized product is flexible enough toprevent stress localization and associated tissue bond failure.Furthermore, star molecules in general will not be preferred since theycontain numerous branches. More numerous branching of the centermolecule is associated with higher liquid viscosity. Furthermore, highlybranched prepolymers will form polymerized products more slowly and withhigher modulus. For example, U.S. Pat. No. 5,578,662 quotes across-linking reaction time of 5 minutes to 72 hours. Both of thesecharacteristics are undesirable when the prepolymer is intended as asurgical adhesive or sealant.

Absorbable Compositions and Particulate Additives

Absorbable prepolymer systems can be composed of discontinuous (solid)and continuous (liquid) parts. The solid part may be absorbable or maynot be absorbable. One of the simplest forms of an absorbable implant isone that mechanically breaks into small pieces without appreciablechemical modification. Fracture of an implant can be seeded orpropagated by the placement of hard centers in the polymer duringformation.

Mixing the liquid polymer with calcium triphosphate particles will afterexposure to fluids or tissue polymerize into an elastic solid containingan inelastic particulate. Movement of the surrounding tissue will deformthe elastic implant. Since the particulate cannot deform, stress willlocalize around these centers and cracks will begin to propagate fromthese centers. In this way, the rate of disintegration and size of thedisintegrated parts can be controlled by varying the particulate size,the modulus of the formed continuous polymer, and the densitydistribution of the particulate.

Non-absorbable solids are well known and include, as examples andwithout limitation, calcium triphosphate, calcium hydroxylapatite,carbon, silicone, Teflon, polyurethane, acrylic and mixture of these.Absorbable solids are well known and include, as examples and withoutlimitation, glycolic acid, glycolide, lactic acid, lactide, dioxanone,epsilon-caprolactone, trimethylene carbonate, hydroxybutyrate,hydroxyvalerate, polyanhydrides, and mixtures of these.

Other absorbable prepolymer liquids can be composed of two continuousmechanically mixed parts. For example, one part may be absorbable andthe other not. Consequently, the absorption of one part results in themechanical disintegration or weakening of the implant. Absorbablecomponents may include liquid forms of cellulose ether, collagen,hyaluronic acid, polyglycolic acid, glycolide and others known in theart.

Exemplary Polymeric Structures

There are several ways in which the above-recited steps can be used toobtain a liquid reactive polymer system. In a simple system, a polymericpolyol with a number of end groups on average greater than two istreated with a slight excess of a LMW-PIC, such as toluene diisocyanate.The reaction product is formed under nitrogen with mild heating,preferably by the addition of the LMW-PIC to the polymer. The product isthen packaged under nitrogen, typically with no intermediatepurification.

In one embodiment, the biodegradable polyol composition includes atrifunctional hydroxy acid ester (e.g., several lactide groupssuccessively esterified onto a trifunctional starting material, such astrimethylolpropane, or glycerol). This is then mixed with a linearactivated polyoxyethylene glycol system, in which the PEG is firstcapped with a slight excess of a LMW-PIC, such as toluene diisocyanate.Then the activated polymer is formed by mixing together the activatedpolyoxyethylene glycol and the lactate-triol. Each lactate triol bindsthree of the activated PEG molecules, yielding a prepolymer with threeactive isocyanates at the end of the PEG segments, and with the PEGsegments bonded together through degradable lactate groups. In theformed implant, the lactate ester bonds gradually degrade in thepresence of water, leaving essentially linear PEG chains that are freeto dissolve or degrade. Interestingly, in this system, increasing thepercentage of degradable crosslinker increases rigidity, swell andsolvation resistance in the formed polymer.

Other polyol systems include hydroxy acid esterified linear polyetherand polyester polyols optionally blended with a low molecular weightdiol. Similarly, polyester and polyether triols esterified with hydroxyacid are useful. Other polyol systems include the use of triol formingcomponents such as trimethylolpropane to form polyols having three armsof linear polyether chains.

Delivery Devices and Methods

In one embodiment, the delivery device possesses a blocking componentfor preventing liquid implant from escaping from the nuclear region of avertebral disc and preferably prevents liquid implant from coating aportion or all of the otomy made to access the nuclear region. Thedelivery device can be used in combination with a hollow fixedinstrument that guides the operational instruments to a selectedlocation in or adjacent to an annular fissure, or other site in thespine in need of repair. The described procedures address minimallyinvasive use, but can be used in open surgeries. A detailed descriptionof an entire apparatus or series of apparatuses for each instance shouldnot be necessary to enable those skilled in the art to make a device forthe treatment methods disclosed herein, since some of the individualcomponents are conventional. The methods can be accomplished withendoscopic instruments, automated surgical systems, or any system withstructural parts that function as set forth herein.

Delivery Device

In one embodiment, a device for delivering the liquid nucleus implant tothe site is an injector. An example of a suitable delivery device 610 isshown in a schematic way (not to scale) in FIG. 2. The deviceillustrated is constructed in the same general manner as anintravascular catheter, although it may be considerably shorter inoverall length. FIG. 2 shows the handle 611, which holds a catheter-likecompound tube 614, which in this embodiment encloses an injection lumen620 terminating at distal tip 616, and an inflation lumen 617terminating in encircling balloon 618. The injection lumen connects to aport 607 near to or within the handle 611 for connecting a polymersource 615, which as illustrated can be a syringe, but could instead bea pump. The balloon 618 and tube 614, when being introduced into thepatient, passes through the lumen 613 of an introducer 612. The balloon618 can be arranged in a collapsed state to facilitate the introductioninto lumen 613. The introducer 612 can be as simple as a hollow tube. Anintroducer can comprise a hollow tube device 612 or a combination of asimple exterior cannula 612 that fits around a tapered obturator 619. Ahollow tube is placed through skin and tissue to provide access into theannulus fibrosus. More complex variations exist in percutaneousinstruments designed for other parts of the body and can be applied todesign of instruments intended for disc repairs. The distal end 621 ofthe introducer will typically be inserted into tissue until it lies at alocation into which the prosthetic is to be formed. A suitable outerdiameter for the tube portion 612 is in the range of 5 to 12 mm. In theillustrated embodiment, the diameter of the collapsed balloon 618 isless than the inner diameter of the tube portion 613.

In one embodiment, the blocking component is tapered distally such thata wider part of the blocking component projects into the nuclear spacewith a diameter greater than the diameter of the opening in the annulus.

In one embodiment, the pressure and/or delivery volume of the liquidimplant is controlled. Control of injection can be provided by placing apressure transducer in a suitable location. With pumps, a pressuresensor can be placed on or in the tube, or at the tip. With a syringe, apressure-sensitive pad can be placed on the proximal end of the plunger,as well as on the tube or in the tip. A pressure sensor can be coupledto a display, or a gauge, and/or can be coupled to a microprocessor forautomatic or semiautomatic control. In the later case, the variance ofpressure with time can be used to help decide when injection has beensufficient.

The delivery device described above uses a balloon to be inflated in acannula 612 or a surgically formed otomy to provide a barrier to implantloss during injection of the liquid nucleus implant into the discnuclear region. The balloon is inflated by attaching an air source 608to a port 609 located on the catheter-like compound tube 614.Alternatively, the blocking means may be any mechanically distensibleinterface that forms a seal between it and a cannula or surgicallyformed passageway. An example of an alternative blocking means isillustrated in FIG. 3. In this instance, the blocking means 622 replacesthe balloon 618 of FIG. 2. The inflation lumen 617 of FIG. 2 is replacedby wire lumen 623. Inside wire lumen 623 is wire 624 attached toactuation hub 625. When actuation hub 625 is turn axially the wire 624is drawn into the hub. The detailed mechanics for achieving this wireretraction are known in the art. Blocking means 622 is comprised of anelastic material with outer diameter less than the inner diameter 613 ofthe cannula 612 of FIG. 2. Blocking means 622 possesses a concentricaxially aligned hole 626 of inner diameter equal to the outer diameterof catheter 614. The blocking means 622 resides on the delivery catheter614 as shown in FIG. 3. The blocking means 622 is held in place bystationary hub 627 and actuation hub 628. A slot 629 in tube 614 allowswire 624 to pull actuation hub 628 toward actuation hub 625. Theactuation hub 625 is rotatable on catheter 614 such that when tension isplaced on wire 624 the blocking means 622 compresses and increases inouter diameter.

In one embodiment, the blocking means 622 prevents liquid implant fromleaving the injection site. The proximal end of the blocking componentcan be flush with the inner layers of the annulus. To accomplish thisthe catheter 614 may be marked for imagining during fluoroscopy toindicate the proximal and distal ends of the blocking means. In anotherembodiment, the blocking component has a tissue engaging surface toprevent slippage.

In the use of some liquid nucleus implants, primarily those that are notfoaming, in one embodiment a third lumen is provided in the deliverycatheter to allow for the passage of displaced air as the nuclear spaceis filled with implant.

In the application of multiple injections the inflation lumen 617 may befilled with a disposable lumen that can be removed after a firstapplication of liquid implant without repositioning the blocking meansand inflation lumen 617. In this case, the disposable lumen can beextended beyond the catheter tip 616 to provide a first smallapplication of liquid implant to coat the inner surface of the annulus,such a disposable lumen can be flexible to contour to and spread evenlyliquid implant upon the inner surface of the annulus.

Methods

There are two common approaches to a vertebral disc. The posteriorapproach is generally an open procedure, where access to the disc doesnot require a cannula or tube through which surgical procedures areperformed. The contra-lateral approach is generally a percutaneousapproach where access to the disc requires a cannula or tube throughwhich surgical procedures are performed. The methods associated witheach of these approaches are different, but both approaches use thedelivery catheters disclosed herein.

The proximal approach is used when the disc annulus has large defects orthe disc is impinging on the spinal cord. In this case the outerdimension of the balloon when inflated should exceed the expected innerdiameter of the otomy to be made in the disc annulus so that a sealedinterface can be formed between balloon and annulus. The diameter of theballoon will typically be between 5 and 12 mm. The balloon may have arigid maximum diameter when inflated or may be elastic. The balloonshape may be dumbbell in axial cross section to help localize it in theotomy of the annulus.

The procedural steps are as follows: 1) surgically expose the portion ofthe disc annulus to be treated, 2) create an otomy in the annulussufficient to allow for removal of part or all of the disc nucleus toprevent further loss of disc nucleus in the case of an annulus defectand to reduce pressure on the annulus in the case of a herniated disc,3) insert the delivery catheter so that the blocking means is flush withthe excavated inner surface of the nucleus/annulus interface, 4) actuatethe blocking means so that the delivery catheter is localized in theannulus, 5) begin injecting nucleus implant to a desired volume orpressure, 6) hold assembly in place until the implant has cured, and 7)deactuate the blocking means and remove the delivery catheter. Generallythe otomy will be left open so that the annulus may heal and seal theimplant within the disc.

The contra-lateral approach is generally a percutaneous approach. It isused when the annulus has a normal shape and generally when a nuclectomyis performed. In the diagnostic phase leading up to the decision toplace a nucleus implant first the integrity of the annulus is assessed.This is done by placing an anchoring guidewire through the annulus wallinto the nucleus of the disc so that various diagnostic and treatmentprocedures may be performed. The guidewire may be employed in directingan injection needle for delivering an indicator solution to the nucleusto assess leakage outside the annulus from the nucleus. Alternativelythe guidewire may be employed in directing means for creating an otomyin the annulus and subsequent removal of nucleus.

In the contra-lateral procedure described here, the guidewire is furtheremployed to deliver a cannula. In FIG. 4A, cranial view, a guidewire 710is position in the nuclear area 711 of a disc 712. The nuclear area mayinclude part of the disc annulus 713. FIG. 4B shows a cannula 714 fittedwith an obturator 715 with a central axial bore 716. The distal end ofthe guidewire 710 is placed into the bore 716 and the cannula/obturatorassembly is advanced along the guidewire 710. The proximal end of theobturator 715 is tapered such that it easily enters the disc annulus 713with a minimal disruption of tissue. The annulus 713 may be prepared forthis operation by placing a slit cut in the annulus centered on theguidewire. Under fluoroscopy the cannula 714 is advanced into theannulus until its proximal end is flush with the outer layers of thedisc nucleus 711. The outer diameter of the cannula 714 is preferably 5mm. The obturator 715 is removed and a 4.5 mm shaver blade 719 isintroduced into the lumen 718 of the cannula 714 as pictured in FIG. 4C.The nucleus is then removed to a therapeutic degree and the evacuatedspace washed of loose debris. The delivery catheter 614 is introducedinto the lumen 718 of the cannula 714 as shown in FIG. 4D. The proximalend of the catheter is positioned flush with the periphery of theevacuated space of the nucleus and the blocking means 720 actuated. Ifthe blocking means is a balloon as shown in FIG. 4D, then a stop-cock721 is attached to inflation port 722 and to the open end of thestopcock is connected to a syringe 723 loaded with either air or liquid.The balloon is inflated by positioning the valve of the stop-cock sothat pressure applied to the syringe 723 delivers fluid volume to theballoon. When the proper volume of fluid is delivered or an appropriatepressure achieved the valve of the stop-cock is closed fixing theballoon 720 in a deployed position. The syringe 724 containing thesingle-part liquid implant is attached to the delivery catheter via luerconnection 725. The delivery catheter is primed by depressing theplunger of syringe 724 to a specified volume position 726 indicated onthe syringe. The medical professional may optionally release thecatheter balloon and subsequently re-inflate to allow for the volumedisplaced by priming the catheter to be released from the nucleus of thedisc 711. Then liquid implant from syringe 724 is injected into thenuclear space 711 until a specified volume or pressure is achieved. Thedispensing syringe 724 may optionally have a pressure sensing device727. After a specified period of time the balloon 720 is deflated andthe delivery catheter 614 removed. A plurality of delivery catheters maybe deployed in this manner to fills regions left unfilled, or to buildpressure in the nuclear space 711 by injecting liquid implant inside ofan already formed implant volume. This may optionally be performed by apiercing needle placed in the center of a formed implant, and additionalliquid implant dispensed into this center. The liquid implant deliveredin this manner would not require a blocking mechanism since the formedimplant provides the blocking.

Optionally, the cannula 714 may be moved distally in the annulus asdepicted in FIG. 5, such that the delivery catheter 614 may be deployedin contact with the annulus tissue 713 and inflated there to provideblockage.

1. A method for treating a defect in a spinal disc nuclear space, comprising: (a) creating an opening by open, percutaneous or laparoscopic techniques to access the defect in the nuclear space; (b) removing a desired amount of tissue from the nuclear space; (c) positioning a delivery catheter through the opening; (d) fluidically isolating the nuclear space by blocking the opening with a blocking component of the catheter; (e) delivering an in-situ curable liquid material through a lumen of the catheter to the nuclear space; and (f) maintaining the isolating until the liquid material has cured.
 2. The method of claim 1, further comprising: (g) removing the blocking component and the delivery catheter; and (h) closing the opening.
 3. The method of claim 1, where the treating comprises one or more of: (i) augmenting or replacing the nucleus pulposus; (ii) reinforcing a wall of the annulus fibrosus; (iii) removing and sealing herniated or bulging portions of a disc; and (iv) closing a defect in the annulus pulposus.
 4. The method of claim 1, wherein the removing in (b) comprises removing one of (i) a portion of the nucleus pulposus, (ii) all of the nucleus pulposus, or (iii) a portion or all of the nucleus pulposus and a portion or all of the inner layers of the annulus fibrosus.
 5. The method of claim 1, wherein the blocking component comprises an expandable balloon surrounding the catheter.
 6. The method of claim 1, wherein the blocking component comprises an elastic collar surrounding the catheter.
 7. The method of claim 1, wherein after (e) a second in-situ curable liquid material is delivered over or into said first cured material, to achieve a desired pressure in the nuclear space.
 8. The method of claim 1, wherein the blocking component isolates the tissues surrounding the opening in the annulus from the liquid implant placed in the nuclear space to provide for the unobstructed growth of the annulus into the space created by the opening.
 9. The method of claim 1, wherein the blocking component is tapered distally such that a wider part of the blocking component projects into the nuclear space with a diameter greater than the diameter of the opening in the annulus.
 10. The method of claim 1, wherein the blocking component has a tissue engaging surface to prevent slippage.
 11. The method of claim 1, wherein the curable liquid material is delivered under pressure sufficient to increase the distance between vertebral endplates adjacent to a treated nucleus.
 12. The method of claim 11, wherein a lumen in the delivery catheter allows for evacuation of gas from the nuclear space as liquid implant is injected.
 13. The method of claim 1, wherein a disposable lumen is placed inside the delivery catheter lumen to allow for multiple injections of liquid implant without repositioning the blocking component of the delivery catheter.
 14. The method of claim 1, wherein the delivering of the curable liquid material in (d) comprises: a first application that coats and seals an inner surface of the annulus fibrosus; and a second application to fill the nuclear space.
 15. The method of claim 15, wherein the second application pressurizes the nuclear space.
 16. The method of claim 1, wherein the curable liquid material foams while it cures and produces a pressure inside the nuclear space independent of the pressure of the delivering.
 17. The method of claim 1, wherein the curable liquid material foams and incorporates any air pockets remaining in the nuclear space to provide substantially complete contact between the inner surface of the annulus and the cured implant.
 18. The method of claim 1, wherein after (b), a sheet is interposed between the nuclear space and the blocking component to provide increased strength to the cured liquid implant after it has cured.
 19. The method of claim 18, wherein the sheet is a mesh.
 20. The method of claim 18, wherein the sheet comprises a cured liquid implant.
 21. The method of claim 18, wherein the sheet has a conical cross section.
 22. The method of claim 1, wherein the curable liquid material comprises: a polyurethane prepolymer comprising a polymeric polyol end-capped with diisocayanate, and a low molecular weight polyisocyanate.
 23. The method of claim 22, wherein the polymeric polyol comprises polyethylene oxide and polypropylene oxide.
 24. The method of claim 23, wherein the polymeric polyol comprises polyethylene oxide in an amount ranging from 70 to 90% by weight and polypropylene oxide in an amount ranging from 10 to 30% by weight.
 25. The method of claim 22, wherein the polymeric polyol comprises 75% polyethylene oxide and 25% polypropylene oxide.
 26. The method of claim 22, wherein the polyurethane prepolymer is a trifunctional polyol capped with diisocyanate, the trifunctional polyol being formed by trimerizing polymeric diols with trimethylol propane.
 27. The method of claim 22, the polyurethane prepolymer has a molecular weight ranging from 4500 D to 5500 D.
 28. The method of claim 22, the low molecular weight polyisocyanate has a molecular weight of 1000 D or less. 